Dosing of iron supplementation for iron‐deficient patients with heart failure: should we prefer more intensive or less intensive repletion targets?
Authors: Milton Packer
Journal: European Journal of Heart Failure (2023)

For a drug to be effective for the treatment of heart failure, physicians must know who should receive it and how it should be started, titrated and maintained. In prescribing the foundational drugs for heart failure and a reduced ejection fraction, physicians rely on the protocol-specified eligibility criteria and guidance about the initiation and continuation of doses that reduced morbidity and mortality. The decision-making process is somewhat different if a drug is administered to achieve a physiological or biochemical effect. Diuretics alleviate fluid retention, and doses are individualized to achieve euvolaemia without worrisome azotaemia or electrolyte imbalances. Potassium supplements and binders are titrated to maintain serum potassium in a desired range. In both examples, the physiological or biochemical marker serves both as a trigger for treatment and as a guide to the titration of therapy. Should the dosing of iron supplementation be guided by biochemical measurements or by regimens that have been shown to improve outcomes? Historically, patients with an absolute iron deficiency (due to poor nutritional intake or gastrointestinal bleeding) were identified by exceptionally low levels of serum ferritin (i.e. <15–25 μg/L).1 However, patients with heart failure are typically iron deficient because of a functional block on the absorption of iron from the duodenum or the release of iron from the reticuloendothelial system, related to inflammation or other cellular stresses that increase both hepcidin and ferritin.2 Consequently, in patients with heart failure, the threshold for serum ferritin in the diagnosis of iron deficiency is increased by 1–2 orders of magnitude on a natural log scale, to <100 μg/L or to <300 μg/L if the transferrin saturation (TSAT) is <20%. However, these shifts do not fully account for the possibility of functional iron deficiency,3 and current ferritin criteria in the identification of iron-deficient patients with heart failure have been questioned.4 Furthermore, the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors distort the ability of conventional iron biomarkers to guide the dosing of iron supplements.2 Therefore, in contrast with diuretics and potassium supplements/binders, the goal of iron therapy is to improve functional capacity and to reduce the risk of cardiovascular death or hospitalization for heart failure, rather than to normalize values for laboratory measurements that have not been clinically validated or may be influenced by coadministration of foundational drugs. As a result, the approach to the correction of iron deficiency should be guided by the design of randomized controlled trials that have shown a benefit of iron supplements on clinically relevant endpoints. Table 1 summarizes the design of the seven completed or ongoing randomized controlled trials of iron supplementation with >100 patients with heart failure.5-11 In six of the seven trials, iron supplementation with ferric carboxymaltose or derisomaltose was initiated during a 1–6 week repletion period, during which patients received as little as 500 mg or as much as 2000 mg of elemental iron, using algorithms that were largely based on haemoglobin and body weight, and not influenced by the severity of iron deficiency. The trials used broadly similar approaches for the initial dosing of iron supplements, but they differed markedly with respect to their recommendations regarding repeated dosing. In four trials, the protocol recommended repeat iron supplementation after the initial repletion period only if patients continued to fulfill the criteria for iron deficiency that had been established at the time of enrolment. If patient had a serum ferritin <100 μg/L or the combination of a TSAT <20% with a serum ferritin <300 μg/L, patients were to receive additional iron supplements (typically, 500 mg of ferric carboxymaltose) at 12, 24 or 36 weeks in the CONFIRM-HF trial,6 at 12 weeks in the EFFECT-HF trial,7 at 12 or 24 weeks in the AFFIRM-AHF trial,8 and every 6 months in the HEART-FID trial.10 The variability in these recommendations was largely related to differences in the trial duration. The total doses of ferric carboxymaltose over the trial duration were 500–3500 mg over 52 weeks in CONFIRM-HF,6 1000–2000 mg over 24 weeks in EFFECT-HF,7 and up to 3000 mg over 52 weeks in AFFIRM-AHF.8 In these three trials, follow-up was truncated at 6 to 12 months, and thus, no guidance about dosing was provided beyond the first year. In striking contrast, three trials recommended repeated dosing with an iron supplement as long as the ferritin levels did not exceed a threshold level that was meaningfully higher than that currently used to identify patients with heart failure who have an iron-deficiency state. FAIR-HF specified repeated iron doses as long as the serum ferritin was not >800 μg/L, if the serum ferritin was not >500–800 μg/L if the TSAT >50%, or if haemoglobin was not >16 g/dl.5 IRONMAN recommended repeat iron dosing unless the serum ferritin was >400 μg/L or the TSAT was ≥25%, but most patients received only one or two doses.9 In FAIR-HF2, patients receive ferric carboxymaltose every 4 months unless the serum ferritin exceeds 800 μg/L or haemoglobin exceeds 16 g/dl.11 Due to its high ferritin threshold and long duration of treatment, it is likely that FAIR-HF2 will deliver the highest cumulative doses of iron of any of the seven trials (Table 1). Are higher doses of iron supplements better than low doses? Both AFFIRM-AHF and IRONMAN reported an effect of iron supplementation on the combined risk of cardiovascular death and heart failure hospitalization, with a p > 0.05 but <0.10. In both trials, the effect was driven by a reduction in heart failure hospitalizations without an effect on cardiovascular death or on ischaemic events. Is the FAIR-HF2 trial likely to yield a more persuasive result than AFFIRM-AHF or IRONMAN due to its greater intensity of iron supplementation? Some might believe that aggressive therapy based on higher ferritin thresholds to allow for repeated dosing with intravenous iron is destined to succeed, based on the results of the PIVOTAL trial.12 This trial randomized patients with anaemia and end-stage kidney disease undergoing maintenance haemodialysis to either a low-dose or high-dose strategy of intravenous iron sucrose, which was given as often as 400 mg monthly. In the low-dose arm, patients received iron supplementation only if serum ferritin levels were < 200 mg/L or if TSAT was <20%, whereas in the high-dose arm, patients continued to receive iron until the serum ferritin was >700 μg/L or the TSAT was ≥40%. Accordingly, after 12 months, patients in the high-dose group had received a median of 2000 mg more iron than the patients in the low-dose group. The mean serum ferritin levels at 1 year were 150–200 μg/L in the low-dose group and 550–600 μg/L in the high-dose group. The primary endpoint for the trial was the composite of death from any cause, non-fatal myocardial infarction or stroke or hospitalization for heart failure. The hazard ratio for the effect of high doses of iron versus low doses of iron on the primary endpoint was 0.85 (95% confidence interval [CI] 0.73–1.00; p = 0.04 for superiority) with a nominally significant effect on all-cause mortality alone (hazard ratio 0.84; 95% CI 0.71–1.00), on fatal and non-fatal myocardial infarction alone (hazard ratio 0.69; 95% CI 0.52–0.93), and on hospitalization for heart failure (hazard ratio 0.66; 95% CI 0.46–0.94). Do these results indicate that intravenous iron should be dosed to a ferritin level higher than used in most heart failure trials to date? The primary goal of the PIVOTAL trial was not to test the efficacy of higher versus lower doses of iron, but to determine if higher iron doses would reduce the requirement of concurrently prescribed erythropoiesis-stimulating agents (ESAs).13 ESAs are known to increase the risk of death and non-fatal myocardial infarction in anaemic patients undergoing dialysis, an effect that is related to the administered dose.14, 15 Interventions that allow for lower dosing with ESAs would be expected to have meaningful clinical benefits independent of any other effects. In fact, in the PIVOTAL trial, the median monthly dose of ESAs was 20–25% lower in patients receiving the high-dose versus the low-dose iron regimen (29 757 IU vs. 38 805 IU per month). The difference in ESA utilization in the treatment arms of the PIVOTAL trial likely explains the observed between-group difference in the occurrence of death and myocardial infarction, since these benefits are not seen when intravenous iron is given to patients with heart failure who are not receiving ESAs. Most patients with heart failure are not poised to benefit from an ESA-sparing effect of high-dose iron therapy. Because of the striking heterogeneity in the dosing regimens used in randomized controlled trials, we do not know how to guide repeat dosing of intravenous iron in patients with heart failure who are deemed to be iron deficient, particularly in those receiving SGLT2 inhibitors.2 A comparison of the results of the HEART-FID trial (using a low ferritin-targeting strategy) and the FAIR-HF2 trial (using a high-ferritin targeting strategy) may provide important insights into this important issue. Conflict of interest: During the past 3 years, M.P. reports personal fees for consulting from Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra.